P1038: TL-895, A FIRST-IN-CLASS, COVALENT BRUTON TYROSINE KINASE INHIBITOR (BTKI) FOR THE TREATMENT OF MYELOFIBROSIS (MF) PATIENTS (PTS) WITH SEVERE THROMBOCYTOPENIA (PLATELETS (PLTS) &lt;50 K/UL)
Authors: Michael Loschi, Laszlo Rejto, Hun Chuah, Marianna Caramella, Jesus Hernández Rivas, Paolo Sportoletti, Viviane Dubruille, Marcelo Bellesso, Stefanie Gröpper, Carl Crodel, Hope Qamoos, Ashley Socotch, Zhuying Huang, Sarah Wall, Jesse Mcgreivy, Wayne P. Rothbaum, Srdan Verstovsek, Francesca Palandri
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Nearly 35% of MF pts have severe thrombocytopenia (TCP) with a shortened median overall survival of 7-15 months (mos) (Masarova 2018, 2020). Most pts present with high symptom burden due to dysregulated cytokines (Tefferi 2011), of which elevated IL-8 impairs megakaryocyte function (Emadi 2005). Treatment with JAK inhibitors (JAKi) can worsen TCP in MF pts, with no effective therapies to improve plt counts. TL-895 is a highly potent, selective, orally available, small molecule inhibitor of BTK and bone marrow tyrosine kinase X-linked (BMX) being studied in MF for its potential to (i) impair stromal adhesion, (ii) disrupt aberrant CD34+ cell trafficking (Nimmagadda 2019), (iii) reduce proinflammatory cytokine-mediated symptoms, and (iv) reverse dysfunctional megakaryopoiesis to improve plt counts. Aims: Safety, efficacy, and tolerability of TL-895 in MF pts with severe TCP. Methods: Cohort 3 of this open-label, global Phase (Ph) 2 study (NCT04640532) enrolled adult pts with JAKi-ineligible MF (plts <50 K/μL, ≥25 K/μL). Pts were randomized to TL-895 150 mg BID (Arm A) or 300 mg QD (Arm B). Eligible pts were symptomatic with intermediate/high-risk MF (DIPSS), ECOG £2 with splenomegaly. The primary objective was the recommended Ph 2 dose (RP2D). Key secondary objectives were Total Symptom Score improvement ³50% by MFSAF v4.0 at Week (Wk) 24 (TSS-50), spleen volume reduction ³35% at Wk 24 by central review (SVR-35) and safety. Plt response was assessed per modified IWG-MRT 2006 criteria (plt increase ≥50% from baseline and >50 K/μL for ≥8 wks independent of plt transfusion [Tefferi 2006]). Results: As of 27 Jan 2022, 11 pts were enrolled in Arm A and five pts in Arm B with median follow-up of 11.7 mos. Complete BTK occupancy (≥95%) was achieved in Arm A at trough (C1D8), but not Arm B which closed early. Arm A is described herein. In these 11 pts, baseline median plt count was 39 K/μL, median spleen volume was 1908 cm3, median TSS was 24.7, and 73% were previously treated with a JAKi (Table 1). Six pts (55%) remain on study and five discontinued due to Grade (Gr) 3 fatigue (n=1), progression (n=2) and investigator decision (n=2). Ten (91%) pts were alive at data cut (median 12.4 mos). At Wk 24, four pts (36%) achieved TSS-50 (Fig. 1), despite no pts achieving SVR-35 (median SVR -5.3%, range -18, 38)). Per modified IWG-MRT criteria, five pts (45%) achieved plt response (≥50% improvement for ≥8 weeks [Fig. 2]), two pts (18%) achieved ≥100% plt improvement with a third pending 8-week confirmation (27%). Median time to plt response was 2.9 mos; median duration was 6.7 mos (range 1.9, 13.1+). Median change in serum IL-8 levels from baseline to Wk 12 was -38% and was associated with plt and TSS response. Median change in circulating CD34+ cells from baseline to Wk 4 was +85%, demonstrating transient cell trafficking due to BTK inhibition. The most common treatment-emergent adverse events were anemia (55%), abdominal pain, nausea and TCP (27% each). Anemia and TCP were the most common Gr 3/4 AEs, regardless of causality, 46% and 27%, respectively (Table 1). Summary/Conclusion: In MF pts with severe TCP, TL-895 provided clinically meaningful improvements in TSS and plt counts that were associated with reductions in IL-8. This is the first clinical proof-of-concept for BTKi in the treatment of MF and supports further investigation in a recently commenced randomized, double blind, placebo-controlled Ph 2b study.Keywords: Thrombocytopenia, IL-8, Myelofibrosis, Bone Marrow Fibrosis